Pseudobases formation

This dimeric formulation also accounts for the thermal disproportionation of the compound into a mixture of 2-methyl-l,2,3,4-tetrahydro-jS-carbohne and 2-methyl-jS-carboline anhydro-base. Normal pseudobase formation (453 R = CHs ) takes place in the case of 9-methyl-3,4-dihydro-j3-carbohne methiodide (452 R = CHg). Neither the dimeric anhydro-base nor the -methyl pseudo-base undergo a base-catalyzed disproportionation reaction to give the 1,2,3,4-tetrahydro-and the l-oxo-l,2,3,4-tetrahydro-jS-carboline in a manner analogous... 

In those few cases where hydration and pseudobase formation parallel each other, the agreement can be traced to the fortuitous circumstance that the structure and electronic configuration of the molecule permit both phenomena to occur simultaneously. Quin-azoline-3-methochloride, one of these rare examples, is discussed in Section III,C, 1. 

Covalent hydration and pseudobase formation in transition metal polypyridyl complexes reality or myth N. Serpone, G. Ponterini, M. A. Jamieson, F. Bolletta and M. Maestri, Coord. Chem. Rev.,... 

The most frequently used method for the preparation of isoquinoline Reissert compounds is treatment of an isoquinoline with acyl chloride and potassium cyanide in water or in a dichloromethane-water solvent system. Though this method could be successfully applied in a great number of syntheses, it has also some disadvantages. First, the starting isoquinoline and the Reissert compound formed in the reaction are usually insoluble in water. Second, in the case of reactive acyl halides the hydrolysis of this reaction partner may became dominant. Third, the hydroxide ion present could compete with the cyanide ion as a nucleophile to produce a pseudobase instead of Reissert compound. To decrease the pseudobase formation phase-transfer catalysts have been used successfully in the case of the dichloromethane-water solvent system, resulting in considerably increased yields of the Reissert compound. To avoid the hydrolysis of reactive acid halides in some cases nonaqueous media have been applied, e.g., acetonitrile, acetone, dioxane, benzene, while utilizing hydrogen cyanide or trimethylsilyl cyanide as reactants instead of potassium cyanide. 

Alkaline solutions of alkylpyridinium salts contain increasing amounts of pseudobases (106 equation 83) in equilibrium with the charged form as the series 1-methylquinolinium, 2-methylisoquinolinium, 10-methylphenanthridinium and 10-methylacridinium is traversed. Such species were first postulated as a result of the observation that alkaline solutions of quaternary salts do not obey the Beer-Lambert law. Pseudobase formation at... 

Stevens et al. (58JCS3067) found that when quinolizinium iodide was treated with silver oxide, or when it was warmed with ION NaOH, there was no evidence of the C-hydroxyla-tion (pseudobase formation) that is characteristic of the methiodides of the azanaphthalenes. Their suggestion that this resistance of the quinolizinium ion is understandable, in that C-hydroxylation would destroy the aromaticity of both rings, is probably correct. 

However, it was observed that if one of the ortho C-H groups in the 1-aryl ring of 122 was absent, then only monocyclization occurred (80JCS(P1)1879). Large specific effects of traces of water on the C- and H-NMR spectra and UV spectra of 124 have been attributed to pseudobase formation, but attempts to trap a pseudobase by Decker oxidation to the oxo form were unsuccessful (830MR649). 

Despite the fact that the concept of pseudobase formation has entered the folklore of heterocyclic chemistry, 15 the example presented by most heterocyclic chemistry texts of a reaction involving this phenomenon has recently been shown to be incorrect (Section V,C). It is only recently that systematic quantitative studies on pseudobase stability have been attempted or that the kinetics of pseudobase-cation equilibration have been investigated in detail. Thus, the current review covers a period in which extensive quantitative studies of pseudobase formation have become available. In addition, work in this area since Beke s earlier review4 has been characterized by the detailed application of spectroscopic techniques to the determination of pseudobase structure and tautomerism. 

The concept of pseudobase formation by heteroaromatic cations is intimately related to the covalent hydration of heteroaromatic molecules16-19 and to Meisenheimer complex formation,20-25 although this relationship has not generally been emphasized in the literature until recently26,27. All such reactions involve the formation of -complexes by nucleophilic addition to electron-deficient aromatic species, and yet, extensive reviews of covalent hydration16-19 and of Meisenheimer complex formation20-25 have neither explicitly recognized their mutual relationship nor considered pseudobase formation. 

In general, relatively dramatic spectral changes occur upon pseudobase formation since nucleophilic addition to an unsaturated carbon atom leads to significant changes in the electronic conjugation of the molecule, particularly if pseudobase formation disrupts the aromatic character of a ring. The pH-dependent spectrum shown in Fig. 1 for the 1-methyl-1,5-naph-thyridinium cation 1 which forms the pseudobase 2 is a typical example. 

The ready reversibility of such spectral changes to the spectrum of the cation upon acidification is an important test to rule out irreversible chemical reactions. In general, spectral techniques similar to those extensively used16,19 for the determination of the site of covalent hydration in a heteroaromatic molecule are also applicable to the determination of the site of nucleophilic addition in pseudobase formation. 

Pseudobase formation by 1,3-disubstituted l,2-dihydro-2-oxopyrimi-dinium cations (5) has been extensively studied by UV and PMR spectroscopies.37 The latter technique is particularly useful in this system in allowing the estimation of the relative amounts of 6 and 7 in the pseudobase mixture... 

Equation (2) stresses the acid-base nature of the cation-pseudobase equilibrium and the pK + value, which is analogous to the pKa value for a Br nsted acid, denotes the pH at which the heterocyclic cation and pseudobase are present at equal concentrations. Experimental techniques for the spectrophotometric or potentiometric determination of pK values for pseudobase formation are identical to the methods for determination of pKa values for Br nsted acids.72... 

The data in Tables I and II may be analyzed in a number of ways nature and number of heteroatoms, size of the heteroaromatic system, substituent effects, etc. Attempts at such analyses of the relationships between pKR + and the structure of the cation are presented in the following sections. As expected, the most general observation is that the most electron-deficient cations are most susceptible to pseudobase formation and have the lowest pKR + values. 

There is no spectral evidence for pseudobase formation by the N-methyl-pyridinium cation in even the most basic aqueous solutions that are attainable. An oil which separates from solutions of this cation in concentrated aqueous base has been identified by PMR and IR spectroscopies as predominantly ionic N-methylpyridinium hydroxide.70 The UV spectra of the IV-methylquinolinium and N-methylisoquinolinium cations are pH-independent below pH 14, but both these cations undergo irreversible reactions in more basic aqueous solutions (Section V,D) so that pK + values are not directly measurable. Based on substituent effects in more highly substituted quinolinium and isoquinolinium cations, pKR+ values of 16.5 and 15.3 have been estimated26 for the N-methylquinolinium and Af-methyl-isoquinolinium cations respectively. The estimate for the latter cation is based on somewhat limited data and should be compared with pKR+ = 16.29, which has been measured in aqueous dimethyl sulfoxide solutions.90,91... 

Further benzologation leads to measurable pvalues for the IV-methyl-acridinium (9.8626) and N-methylphenanthridinium (11.9441) cations however, pKR+ > 14 in aqueous solutions of the N-methyl cations of both the 5, 6- and 7, 8-benzoquinolines.41 The loss in resonance energy upon pseudobase formation is expected to be one of the major factors involved in considerations of the relative susceptibilities of heterocyclic cations to pseudobase formation. A rather crude, but informative, calculation of the loss in resonance energy (AR) upon pseudobase formation has been attempted for each of the above cations. 

The details of the estimates of the loss of resonance energy upon pseudobase formation are outlined in Table III.136 139 These estimates are based... 

Estimates of Loss of Resonance Energy on Pseudobase Formation... 

Heteroaromatic cations containing oxygen, sulfur, or selenium ring heteroatoms are far more susceptible to pseudobase formation than the corresponding AT-methyl cations. A comparison of data for structurally related cations is given in Table IV. It is clear that in most cases pKR + values fall in the order O < Se < S NMe, and a linear relationship of unit slope exists between pKk+ values for at least two series (20 and 21) of cations (Fig. 2). The pKR + values reported81 for the linear tricyclic system 22 are unusual in that they fall in the order Se < O < S and furthermore suggest that in these cases 22 are less susceptible to pseudobase formation than their isomers 21, which is unexpected in view of the relative pKR,... 

Pseudobase formation by the pyrylium, thiopyrylium, and selenopyrylium cations is complicated by ring-opening reactions (Section V,A) which preclude a simple direct measurement of pKR + for these cations. In a kinetic study, Williams80 has found the ring opening of 2,4,6-trisubstituted pyrylium cations 23 to be controlled by pKa values in the range of 5.0-6.7 for R2,... 

R4, R6 = Me or Ph. These p/Ca values were not assigned, and the most likely explanation is that these are actually pKR+ values for pseudobase formation by these cations. Such an assignment indicates that pKR is somewhat less than 5 for the unsubstituted pyrylium cation which is consistent with pKr+ >6 which has been estimated81 for the thiopyrylium cation. 

Various isolated examples of pKR + values for other heteroaromatic systems are given in Table I. The similarity in pKR + values for the isomeric 1-, 2-, 3-, and 4-selenaphenanthrene cations further supports the preceding inference that the change in resonance energy upon pseudobase formation is the major determinant of pKR+. 

The increased susceptibility to pseudobase formation for O-heterocyclic relative to the corresponding N-heterocyclic cations that was noted above for the aromatic series is also seen in the l//-isobenzofurylium (25 X = O) and N-phenyl 1 //-isoindolium (25 X = NPh) series in Table II. For these cases ApKR. (NPh - O) 11.5, which may be converted to ApXR. (NMe - O) % 15.5 using the difference noted previously for N-methyl- and N-phenyl-3,4-dihydroisoquinolinium derivatives. This difference is in reasonable agreement with ApXR + (NMe - O) % 18.5 observed for aromatic cations (Table IV). The low stability of the cation relative to the pseudobase for O-heterocycles is also present in the 2H-furylium cations (26). Although... 

A number of attempts have been made to correlate pXR for pseudobase formation with substituent effects expressed as Hammett a or Taft a values. 

The major factor contributing to the magnitude of p in these systems is the neutralization of the charged nitrogen atom of the cation upon pseudobase formation. Thus, the values of p (pKR + ) for N-substituted cations are very similar to p values for the deprotonation of ammonium ions (e.g., p = 3.3 for the acid dissociation constants of tertiary ammonium ions145). Similarly, the p values of Eqs. (4a) and (6a) are similar in magnitude to p = 1.05 for the acid dissociation of ring-substituted benzylammonium ions (27). 46... 

It should be noted that, in principle, correlation equations such as (3)-(7) for the influence of N-substituents on the equilibrium constants for pseudobase formation should allow the estimation of the extent of covalent hydration of the parent nitrogen heterocycle in aqueous solution. Thus using a = 0.49 for H and the appropriate correlation equation, pKR+ for pseudobase formation from the N-protonated parent heterocycle can be estimated. 

Equations (8)—(16) indicate that substituents in the homocyclic ring of quinolinium, benzopyrylium, benzothiopyrylium, and isobenzothiopyrylium cations influence pKR for pseudobase formation in the heterocyclic ring via p values in the range 4.9-6.9. The particular type of charge neutralization upon pseudobase formation is the major determinant of the magnitude of p. The observed p values are considerably larger than p = 2.81 for the acid dissociation of ring-substituted anilinium ions (31)148 which can be considered as the simplest... 

In general, cation-pseudobase equilibration is quite rapid in aqueous solution, and the use of the stopped-flow or temperature-jump techniques is usually required for the measurement of the rates of pseudobase formation from, and decomposition to, the cation. The presence of a large substituent, such as a phenyl ring, at the site of hydroxide ion addition does slow the rate of equilibration sufficiently to allow kinetic measurements by normal spectrophotometric techniques.92... 

Thus pseudobase formation occurs via nucleophilic attack of a molecule of water on the cation at low pH or via attack by hydroxide ion in more basic solutions, or the kinetic equivalents of these mechanisms. More detailed consideration of the mechanisms of these reactions is given in Section IV,B. 

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